Synthesis of Aryl Glycines by the α Arylation of Weinreb Amides

Hirner, Sebastian; Panknin, Olaf; Edefuhr, Magnus; Somfai, Peter

doi:10.1002/anie.200704689

Cited by 31 publications

(7 citation statements)

References 28 publications

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“…Very recently, an unusual and interesting product arising from the sequential treatment of the glycine-based WA 317a with lithium diisopropylamide and phenylmagnesium bromide led to an efficient protocol for the a-arylation of glycine (Scheme 70). 128 The observation of the demethoxylated product 318a is not surprising as it arises merely from an E2 elimination reaction, as observed by Graham. 7a It was the formation of 318b that hinted towards the possibility of a-arylation.…”

Section: Miscellaneousmentioning

confidence: 74%

The Growing Synthetic Utility of the Weinreb Amide

Balasubramaniam

Aidhen

2008

Synthesis

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N-Methoxy-N-methylamide, popularly addressed as the Weinreb amide, has surfaced as an amide with a difference. This amide has served as an excellent acylating agent for organolithium or organomagnesium reagents and as a robust equivalent for an aldehyde group. These two aspects have been exploited exhaustively in various synthetic endeavors. This review presents the growing synthetic utility of the Weinreb amide not only in academic circles, but also its popular use on kilogram scale by various pharmaceutical industries across the globe.

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Section: Miscellaneousmentioning

confidence: 74%

The Growing Synthetic Utility of the Weinreb Amide

Balasubramaniam

Aidhen

2008

Synthesis

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“…So as to establish the viability of the above strategy (Scheme ), we first examined a simplified system that lacked the α‐side‐chain (i.e., R=H). O ‐Alkylation of the bis allylic alcohol 2 (Scheme , obtained by addition of vinylmagnesium bromide to 3‐methyl‐2‐butenal), using the α‐bromo Weinreb amide 3 (prepared from bromoacetyl bromide and N , O ‐dimethylhydroxylamine), proceeded in modest yield. Subsequent addition of vinylmagnesium bromide gave the acid‐labile enone 4 .…”

Section: Resultsmentioning

confidence: 99%

Aruncin B: Synthetic Studies, Structural Reassignment and Biological Evaluation

Ribaucourt

Towers

Josa-Culleré

et al. 2017

Chemistry A European J

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A ring‐closing alkene metathesis (RCM)/ oxyselenation‐selenoxide elimination sequence was established to the sodium salts E‐ and Z‐25 of the originally proposed structure for the recently isolated cytotoxin aruncin B (1), as well as to the sodium salt Z‐34 of a related ethyl ether regioisomer; however, none of their corresponding free acids could be obtained. Their acid sensitivity, together with detailed analysis of the spectroscopic data indicated that profound structural revision was necessary. This led to reassignment of aruncin B as a Z‐γ‐alkylidenebutenolide Z‐36. Although a related RCM/ oxyselenation‐selenoxide elimination sequence was used to confirm the γ‐alkylidenebutenolide motif, a β‐iodo Morita‐Baylis–Hillman reaction/ Sonogashira cross‐coupling‐5‐exo‐dig lactonisation sequence was subsequently developed, due to its brevity and flexibility for diversification. Aruncin B (36), together with 14 γ‐alkylidenebutenolide analogues, were generated for biological evaluation.

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“…Improved strategies to prepare the β-hydroxyester intermediates are described in Scheme . Compounds 42 – 47 were synthesized from the corresponding phenols and 2-bromo- N -methoxy- N -methylacetamide, which was obtained from 2-bromoacetyl bromide and N , O -dimethylhydroxylamine hydrochloride . The corresponding β-hydroxyester intermediates were prepared by condensation of 42 – 47 with the enolate of ethyl acetate.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 42−47 were synthesized from the corresponding phenols and 2-bromo-N-methoxy-N-methylacetamide, which was obtained from 2-bromoacetyl bromide and N,O-dimethylhydroxylamine hydrochloride. 26 The corresponding β-hydroxyester intermediates were prepared by condensation of 42−47 with the enolate of ethyl acetate. The aryloxanyl pyrazolones (13−19) were obtained by treatment of the β-hydroxyester intermediates with hydrazine.…”

Section: ■ Introductionmentioning

confidence: 99%

ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis

Chen

Benmohamed²,

Kim

et al. 2011

J. Med. Chem.

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Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD1) induced toxicity and aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic lead for the treatment of this neurodegenerative disorder.

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Synthesis of Aryl Glycines by the α Arylation of Weinreb Amides

Cited by 31 publications

References 28 publications

The Growing Synthetic Utility of the Weinreb Amide

The Growing Synthetic Utility of the Weinreb Amide

Aruncin B: Synthetic Studies, Structural Reassignment and Biological Evaluation

ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis

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